Speedball (heroin/cocaine) addiction is a distressing public health concern for which there currently is no approved medication. Preclinical evidence suggests that 2 adrenergic agonists may reduce addiction-related effects of heroin and cocaine in laboratory animals, suggesting that they also may be particularly effective in attenuating effects of heroin/cocaine 'speedball' combinations. In response to PA 08-186, which calls for research to develop pharmacotherapies for polydrug addiction, we propose to evaluate the ability of 2 agonists to reduce the abuse- and relapse-related effects of speedball combinations in nonhuman translational models of drug addiction. First, drug discrimination and observational procedures will be used to establish proper temporal and dosing parameters for a series of novel 2 agonists that differ in 2 adrenoceptor selectivity and have favorable side-effect profiles compared to the FDA-approved drug clonidine. This information will guide our studies of how acute and chronic treatment with 2 agonists alters the reinforcing strength and intake of speedball combinations using a choice procedure that incorporates concurrently available second-order schedule of i.v. drug injection and food reinforcement. A major problem in drug addiction is that relapse in abstinent individuals can be triggered by a variety of stimuli including exposure to drugs, drug-related cues, or stressful events. To address this problem, separate studies will be conducted to determine how 2 agonists modify the ability of speedball injections, speedball-associated cues, or stressful stimuli to trigger drug- seeking behavior. Finally, chronic treatment studies with selected 2 adrenergic agonists will be conducted to determine whether tolerance occurs to the sedative or other observable side-effects of selected 2 agonists during repeated administration. We expect our research to identify 2 agonists that effectively attenuate the reinforcing effects of speedball self-administration and inhibit the impact of relapse-related triggers to drug-seeking. These findings will provide essential preclinical information to guide further development of 2 agonists as candidate pharmacotherapeutics for speedball addiction.